Cerebrum

The Creation of Psychopharmacology

Despite its title, David Healy’s new book The Creation of Psychopharmacology takes anything but a creationist’s view of the discovery of psychiatric drugs. Its thesis is that the development of drugs to treat psychoses, regulate mood, and alter behavior is evolutionary: proceeding in ﬁts and starts, with no end of turns and reversals; shaped by the selective pressures of society’s views on mental illness; and driven by the proﬁt-seeking of big pharmaceutical companies.

Healy traverses much of the same ground covered in his ambitious and provocative 1998 book, The Antidepressant Era, but here he focuses especially on the discovery of chlorpromazine (Thorazine) in 1952, which he sees as the deﬁning moment in psychopharmacology. The Creation of Psychopharmacology not only chronicles the process of drug discovery and development, but illustrates how the application of new therapeutics for psychiatric disorders is, by its nature, linked to prevailing social, cultural, and economic forces. This is an ambitious undertaking, requiring Healy to interweave scientiﬁc advances with social and philosophical trends, including the changing perspectives of medicine and psychiatry on mental illness.

SERENDIPITY

The emergence of psychopharmacology has been punctuated by spontaneous, unexpected events that have catalyzed the birth of most antipsychotic and antidepressant medications. New drugs appear to arise as much by happenstance as by intention—even chlorpromazine, which was the first major pharmacological treatment for psychosis and the one that ushered in biologically based psychiatric treatments.

Healy’s theme of serendipity in major therapeutic breakthroughs comes through loud and clear. The drug’s chronology began in the latter part of the 19th century, when German chemists in the aniline dye industry synthesized the ﬁrst series of phenothiazine compounds based on the structure of methylene blue dye. These compounds reappeared in the 1940s, when, in pursuit of novel anti-parasitic agents, the French pharmaceutical company Rhône-Poulenc looked into whether the synthetic compounds might have more potent antiseptic actions than methylene blue. Another division of the company learned of the compounds, tested them as antihistamines, and noted that they also appeared to have sedative properties. Subsequently, French clinicians administered a chlorinated phenothiazine, chlorpromazine, to psychotic patients as an adjunct to a cold-induced “hibernation” therapy. When nurses on the ward ran out of ice, however, they noticed that the patients improved dramatically whether or not they were chilled. Here, as in The Antidepressant Era, Healy’s theme of serendipity in major therapeutic breakthroughs comes through loud and clear.

FROM SALVATION TO “STRAIGHT JACKET”

Healy is most compelling when he describes how historical events shaped the evolution of psychopharmacology. His story moves back and forth in time, interweaving the contemporary perspectives of the lead scientists, clinicians, and social thinkers. In many cases, Healy relies on interviews with those scientists and clinicians, giving us a perspective that is both authentic and personal. The creation of psychopharmacology parallels the history of psychiatry itself and reveals the tension between biological psychiatrists, who perceive mental illness as a disorder of brain chemistry, and psychoanalysts, who emphasize the psychological causes and dynamics of a disorder.

Consider the shift in views of chlorpromazine since its creation. The compound was developed in the 1950s, when chemical companies began marketing a range of new pesticides, antibiotics, and plastics to give us, in the slogan of one company, “better living through chemistry.” But several developments soon intervened to inspire uneasiness with this modern vision of science conquering the perils of nature, especially the tragic birth defects associated with thalidomide in Europe and the publication in 1962 of Rachel Carson’s Silent Spring. At the same time, it was becoming apparent that a common, disabling side effect was associated with long-term antipsychotic drug therapy: a movement disorder called “tardive dyskinesia.” Appearing in patients who had discontinued antipsychotics, this involuntary movement syndrome was a visible sign that the treatment could be as debilitating as the disease.

Ken Kesey, in his book One Flew Over the Cuckoo’s Nest, portrayed a psychiatric ward where drugs and electroconvulsive therapies are used to control patients. Here, insanity became a metaphor for the oppressiveness and inhumanity of a modern technological society. Visions of the physical therapies previously in favor for treating mental illness re-emerged and became symbolic of a darker age: the disturbing aspects of psychosurgery, the unvalidated application of insulin coma therapy, and the controversy that even now is associated with electroconvulsive shock therapy. Within less than two decades, chlorpromazine had made the transition from psychiatry’s magic bullet to the equivalent of a chemical straightjacket. Healy captures the essence of these turbulent years, giving us an important lesson on how rapidly and resoundingly social and political movements can change how we perceive ourselves and even how we construe the essence of disease.

THE DOWNSIDE

Healy certainly views modern pharmacological therapies as long strides toward dealing with mental illness; but he also relates a cautionary tale to remind us that change is not always progress. For example, one treatment may supplant another not because it is an improvement, but as a result of society’s perceptions and market forces. Healy offers the example of insulin coma therapy (ICT), a treatment for schizophrenia that involved using insulin to induce a hypoglycemic coma often associated with convulsions. (A Beautiful Mind, the recent Academy Award winning ﬁlm on the life of the brilliant game theorist John Nash, vividly portrays the use of ICT in treating schizophrenia.) How ICT might beneﬁt patients was never established; its use declined rapidly as clinicians embraced the safer, more convenient use of chlorpromazine. Healy’s interpretation here deviates from the mainstream, since he asserts that recent research suggests ICT may have been effective, perhaps through a placebo effect or because it made the patient more receptive to psychotherapy.

He argues, more broadly, that many treatments for psychiatric disorders work because they are inherently nonspeciﬁc. A case in point is the class of antidepressants known as SSRIs (selective serotonin reuptake inhibitors). The effectiveness of treatment with these drugs can be difﬁcult to assess, and yet they have been demonstrated to be useful for treating not only depression but a spectrum of other conditions, among them obsessive-compulsive disorder, panic disorder, post-traumatic stress, and social phobia. Healy’s concern is that while many psychiatric disorders are “dimensional” (deﬁned by the degree and severity of a set of symptoms), and thus may not ﬁt well into a narrowly deﬁned disease category, most therapeutic drugs have been developed precisely to treat a speciﬁc disease— not a patient with a particular cluster of symptoms of varying severity. Some of his objections invite skepticism, but they do instruct us in the potential perils of mandating a drug for a speciﬁc use, which is particularly critical in light of the impact of managed care on the practice of psychiatry. In a world of third-party health insurers, where diseases are discretely categorized and the drugs to treat them must generate reproducible outcomes with limited risk, therapies may easily fall outside of these narrow criteria and so be denied to the patient.

In considering the discovery of brain receptors for both neurotransmitters and drugs, Healy illustrates how the science, or “Big Science” as he refers to it, fueled the drive for speciﬁcity. It is a lively story with an interesting cast. In the 1880s, Robert Koch outlined a bacteriologic model of disease in which disorders could be explained by speciﬁc lesions produced by a deﬁnable agent. Extending this concept, his colleague, Paul Ehrlich, proposed that a pharmacological “magic bullet” could be made to target and eliminate the pathogen. In psychopharmacology, the targets for these magic bullets would be receptors that bind neurotransmitters and hormones and mediate their actions. If drug therapies that target the appropriate receptor could be matched with the relevant syndrome, then positive, reproducible results should be achieved. Healy comments that “the receptor vision quickly developed beyond a theory of how some drugs might work into a philosophy of how all therapies should work”—and today’s psychopharmacological revolution was born.

MARKET FORCES

But, to return to our story, Healy contends that, following the backlash of the “anti-psychiatry” movement in the 1960s, some 20 years passed before any significant new medications were developed. Why? He cites multiple factors. Legislation in 1951 enlarged the reach of the Food and Drug Administration (FDA), giving it the power to decide what drugs would be available “by prescription only.” Then, in 1962, sparked by the thalidomide crisis, the Kefauver-Harris amendment charged the FDA with the additional responsibility of passing judgment on the efﬁcacy of both over-the-counter and prescription drugs. Now a drug was not simply expected to be safe; it had to produce demonstrable beneﬁcial effects that far outweighed any potential risks in the treatment. As a consequence of these regulatory measures, drugs would have to be developed for speciﬁc disease indications so that speciﬁc beneﬁts could be shown. Moreover, their efﬁcacy and safety would have to be validated in clinical trials, and they would be available only by prescription.

This huge empowerment of the FDA ushered in the era of what is called “evidence-based medicine,” and what Healy refers to as the “medico-pharmaceutical complex.” Standardized protocols were developed to evaluate the effects and outcomes of drug therapy on psychiatric disorders. These “randomized clinical trials,” Healy argues, benefit the pharmaceutical industry because they allow drugs to be targeted to the broadest possible markets. In other words, a pharmaceutical company can decide what product it wants to introduce, then develop the market for it. Conditions that may not have been viewed as problems in the past are found to be treatable by a given compound, and so achieve the status of a disease. Is this what we are seeing in the explosion of drugs used to treat behavioral disorders in children, including Ritalin (methylphenidate) and antidepressants? The use of rating scales to assess behavior by, for example, school psychologists, draws attention to those behaviors that lie outside a predetermined range. This becomes a rationale for drug treatments to bring children back inside appropriate norms. The analysis itself defines the disease.

These are interesting and provocative ideas, but there are many points in The Creation of Psychopharmacology where Healy crosses the line from healthy skepticism to cynicism. For example, he points out that only drug companies have sufficient resources to identify and produce new drug molecules, but he has few suggestions on how to support an environment in which new drugs are developed to treat the patient, rather than an arbitrary disease state. Limiting the amount of time a drug is given prescription status, as he proposes, might appear to be a good idea, but it opens the way for the use of potentially harmful drugs without medical supervision. It is also hard to reconcile Healy’s advocacy of making psychoactive drugs more widely available with his conviction that some antidepressant medications may trigger as many suicides as they prevent— a fact he believes is being obscured by the drug industry.

The Creation of Psychopharmacology also suggests that too much of our current scientific and clinical understanding of the latest generation of antipsychotic compounds rests on information selectively provided by drug companies. But this dismisses the substantial contributions of research sponsored by the government and nonprofit organizations, as well as overlooking several decades of research sponsored by the National Institutes of Mental health on the epidemiology, genetics, clinical course, and treatment of mental disorders.

Healy envisions a future where “a Brave New World...is shaped not just by new drugs created, but by an almost Orwellian capacity to control the ﬂow of information,” where neither clinicians, nor patients, nor scientiﬁc discovery drives the development of new therapies for mental disorders. The most optimistic among us will not always agree with his prophecies, but if there is one lesson we can learn from The Creation of Psychopharmacology, it is that the landscape will indeed change. Technological and cultural forces are poised to transform and shape how we discover and employ drugs in treating disorders of the mind. Some strategies will build on concepts of the past: for example, the development of drugs to treat anxiety and/or depression that are aimed at new biological targets. Others will use brain imaging to understand drug action. And the new ﬁeld called pharmacogenomics will use detailed maps of our individual genes to customize how we develop and prescribe drugs.

In the opening line of the novel The Go-Between, L.P. Hartley wrote “The past is another country—they do things differently there.” Perhaps that is how we will look back on the creation of psychopharmacology.

EXCERPT

Beyond biological differences between the sexes, there lie differences in temperament, differences between introverts and extraverts, for instance. There is considerable evidence that such differences have a biological basis. Jerome Kagan has argued cogently for a recognition of the role of temperamental inputs to culture, even proposing that many of the world's major religions owe their distinctive features in part to the biology of those races that gave rise to them. And it seems likely that a majority of philosophers and ethicists in Western cultures have been introverts. In these cultures, the brooding and melancholic Satan of Milton’s Paradise Lost often seems a more substantial and heroic figure than God. How much has this cast of mind biased our ethical and philosophical systems? What would some of these figures have thought of the world if they had been made more sanguine by Prozac?

The interface between a pharmacological management of temperament of this kind and morality poses a set of interesting questions. On a practical level, society and medicine have been through this debate with the development of cosmetic surgery. We appear to have plumped for some version of the concept of Moral Luck when handling the issues. In brief, it is obvious that certain individuals possess benefits and resources that others do not have. It is also reasonably obvious that others are likely to attribute better moral qualities to an individual with a sunny and winning temperament than to someone with an irritable and obsessional personality. What is less obvious is that these attributions may in turn contribute significantly to, or all but determine, the morality of an individual's behaviors. Assessments of the morality of an individual's behaviors may therefore need to take into account the head start that some people have.

Now, take an individual in a stressful work environment. Should she struggle to change the environment? Many would argue she should, in part because some people do. Aside from the fact that this is likely to be a romantic assessment, it needs to be pointed out that changing such an environment will be easier for people who are less sensitive to interpersonal nuances than others. These fortunate individuals may not get this way by virtue of morally praiseworthy character building; they are commonly this way by virtue of their genes. The issues are the same as those facing subjects trying to hold onto work in a marketplace that rewards the physically attractive. Physical attractiveness does not derive from personal effort. But when the cosmetic means to enhance attractiveness become reliably available, the history of cosmetic surgery points strongly to the likelihood that these means will be eagerly embraced.

Are people likely to be alienated by such cosmetic interventions? Cosmetic surgery once was a symbol of alienation. Now, the growing acceptance of cosmetic procedures demonstrates just how potently markets can define the meaning of our experiences. That being the case, it is extremely important that we know what drug companies are up to and that we understand the consequences of the regulatory arrangements put in place to manage the production and use of drugs. As recently as the 1900s, the regulation of drugs was viewed as an industrial matter, differing little from the process of regulating and labeling foodstuffs, but it is now clear that much more fundamental issues are at stake—at least within psychiatry.

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Bill Glovin, editor Carolyn Asbury, Ph.D., consultant

Scientific Advisory Board Joseph T. Coyle, M.D., Harvard Medical School Kay Redfield Jamison, Ph.D., The Johns Hopkins University School of Medicine Pierre J. Magistretti, M.D., Ph.D., University of Lausanne Medical School and Hospital Robert Malenka, M.D., Ph.D., Stanford University School of Medicine Bruce S. McEwen, Ph.D., The Rockefeller University Donald Price, M.D., The Johns Hopkins University School of Medicine